The 2006–07 season saw growing media speculation that Mourinho would leave the club at the season's conclusion, due to alleged poor relations with owner Roman Abramovich and a power struggle with sporting director Frank Arnesen and Abramovich advisor Piet de Visser. Mourinho later cleared doubts regarding his future at Stamford Bridge, stating that there would only be two ways for him to leave Chelsea: if Chelsea were not to offer him a new contract in June 2010, and if Chelsea were to sack him.
Later during the season, Mourinho maintained a strongly critical position against refereeing in Italy, which reached its peak during the league game on 22 February 2010 against Sampdoria, which ended in a 0–0 tie, with two Inter players being sent off in the first half. At the end of the first half, Mourinho made a handcuffs gesture towards a camera which was considered by the Italian Football Federation as violent and critical of the refereeing performance, and caused a three-game ban against the Portuguese coach. Also, his difficult relationship with young striker Mario Balotelli and the team's loss of form that led Inter to achieve only seven points in six games (with three of those games, including a shock 1–3 defeat at the hands of Sicilian minnows Catania, happening during Mourinho's ban) were heavily criticised by the media and pundits. Despite this, Mourinho achieved what was hailed as one of his career highlights after Inter managed to progress to the Champions League quarter-finals by defeating his former team Chelsea in both legs (2–1 win at San Siro, then followed by a 1–0 win at Stamford Bridge).
On 6 April 2010, José Mourinho became the first manager in history to take three different teams to the semi-finals of the Champions League (this record was equalled by Bayern Munich manager Louis van Gaal a day later) after Inter managed to overcome CSKA Moscow 1–0 in Russia in the second leg of their quarter-final tie, which ended 2–0 on aggregate. Wesley Sneijder's goal in the sixth minute proved the difference in a match played in laid-back style. This marked the first time in seven years that Inter managed to make it to the semi-finals of the competition. On 13 April, Inter continued their good season, having managed to reach the Coppa Italia final, for the first time under Mourinho, by beating Fiorentina 1–0 away (2–0 on aggregate).
On 28 April 2010, José Mourinho reached the Champions League final for the second time in his career after Inter beat holders Barcelona 3–2 on aggregate, despite losing 1–0 at Camp Nou (which Mourinho called "the most beautiful defeat of my life"). This brought Inter back into a European Cup final 38 years after their last (a defeat by Ajax). Mourinho was involved in a brief scuffle with Barcelona goalkeeper Víctor Valdés while attempting to join in the Inter celebrations. Mourinho afterwards stated that "anti-Madridismo" had motivated the Barça fans, suggesting that they were obsessed with reaching the final and winning the tournament in their arch-rival's home ground. Marca proclaimed that Mourinho had passed the test to become the next head coach of Real Madrid, as their fans celebrated the elimination of Barcelona.
On 2 May, after a 2–0 away win at Rome against Lazio, Inter almost secured the Serie A title. On 5 May 2010, the team won the Coppa Italia, defeating Roma 1–0, and on 16 May 2010, Inter beat Siena 1–0 to secure the domestic double, accomplishing the feat of winning all trophies available for a manager in the Serie A.
On 22 May 2010, Inter won the 2010 Champions League after beating Bayern Munich 2–0, and in doing so became the first Italian club to complete the treble, with Mourinho personally celebrating the second Champions League title in his managerial career.
After days of discussions between Real Madrid and Inter, a world record breaking compensation package was successfully agreed on 28 May 2010, and Mourinho was consequently released by Inter.
On 28 May 2010, it was confirmed that Mourinho would take over from Manuel Pellegrini at the Santiago Bernabéu Stadium. On 31 May 2010, Mourinho was unveiled as the new manager of Real Madrid after signing a four-year contract, and became the 11th manager in the past seven years at the club. Mourinho was appointed sporting manager as well as first-team coach, and he was referred to as a Galáctico (a term more often used for star players instead of coaches).
On 29 August 2010, Real Madrid drew 0–0 at Mallorca in Mourinho's first La Liga game as manager. When asked about all the missed opportunities against Levante in La Liga and Auxerre in the Champions League, Mourinho said, "One day some poor rival is going to pay for the chances we've missed today." The following match at the Bernabéu ended with a 6–1 victory over Deportivo de La Coruña. The following league games confirmed Mourinho's statement, defeating Málaga 4–1 and Racing Santander 6–1.
On 29 November 2010, Mourinho's Madrid were defeated in his first Clásico encounter against Barcelona. The match, held in Camp Nou, ended 5–0 to the hosts, with Real Madrid director Florentino Pérez regarding it the worst game in the history of Real Madrid. Sporting director Jorge Valdano also criticised Mourinho for his "inability to bring a major correction to the game" and "not leaving his bench for the [majority] of the match". When asked by a media reporter, however, Mourinho refused to call the loss a "humiliation".
On 30 November 2010, Mourinho was fined £33,500 for appearing to instruct Xabi Alonso and Sergio Ramos to attempt to receive a tactical second yellow card in the 4–0 Champions League win against Ajax. He was also banned for two Champions League matches, the second of which is suspended for three years. On 22 December 2010, Mourinho won a match by the widest margin in his career, winning 8–0 against Levante, also of La Liga, in the first leg of their quarter-final of the Copa del Rey.
Mourinho is widely regarded by several players and coaches to be one of the best managers of his generation and one of the greatest ever managers. In 2010, Pep Guardiola described Mourinho as "probably the best coach in the world". Chelsea midfielder Frank Lampard has stated that Mourinho is the best manager he has ever worked for.
In a 2010–11 Champions League match at Ajax in November 2010, late in the match when Real Madrid were leading 4–0, two Real Madrid players received late second yellow cards related to time-wasting. The result of this meant they were suspended for the final group match even though Madrid would come first in the group, but would benefit by entering the round of 16 without any accumulated yellow cards. It was suggested after an investigation by UEFA that this was a deliberate ploy under Mourinho's instruction via two players in a substitution. As a result, UEFA charged Mourinho along with the four related players with improper conduct regarding the dismissals. Although Mourinho denied the allegations, he was fined £33,500 and received a one-match Champions League ban.